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Ethnopharmacological Relevance: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by non-specific inflammation. Managing UC presents significant challenges due to its chronic nature and high recurrence rates. Indigo naturalis has emerged as a potential therapeutic agent in clinical UC treatment, demonstrating advantages in alleviating refractory UC and maintaining remission periods compared to other therapeutic approaches., Aim of Review: This review aims to elucidate the potential mechanisms underlying the therapeutic effects of indigo naturalis in UC treatment, assess its clinical efficacy, advantages, and limitations, and provide insights into methods and strategies for utilizing indigo naturalis in UC management., Materials and Methods: Comprehensive data on indigo naturalis were collected from reputable online databases including PubMed, GreenMedical, Web of Science, Google Scholar, China National Knowledge Infrastructure Database, and National Intellectual Property Administration., Results: Clinical studies have demonstrated that indigo naturalis, either alone or in combination with other drugs, yields favorable outcomes in UC treatment. Its mechanisms of action involve modulation of the AHR receptor, anti-inflammatory properties, regulation of intestinal flora, restoration of the intestinal barrier, and modulation of immunity. Despite its efficacy in managing refractory UC and prolonging remission periods, indigo naturalis treatment is associated with adverse reactions, quality variations, and inadequate pharmacokinetic investigations., Conclusion: The therapeutic effects of indigo naturalis in UC treatment are closely linked to its ability to regulate the AHR receptor, exert anti-inflammatory effects, mcodulate intestinal flora, restore the intestinal barrier, and regulate immunity. Addressing the current shortcomings, including adverse reactions, quality control issues, and insufficient pharmacokinetic data, is crucial for optimizing the clinical utility of indigo naturalis in UC management. By refining patient-centered treatment strategies, indigo naturalis holds promise for broader application in UC treatment, thereby alleviating the suffering of UC patients., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Preliminary studies showed that Shanlameiye granules are derived from Chimonanthus nitens Oliv. Leaves ameliorate inflammatory responses in mice with Allergic Rhinitis (AR). The essential oil from Chimonanthus nitens Oliv. Leaves (CLO) have been identified as the key active substances in these granules. However, whether CLO constitutes the primary mechanism for the mitigation of AR-related inflammation by these granules has not yet been investigated., Aim of the Study: This experiment was to validate the effects and mechanism of CLO on inflammatory responses in RAW264.7 cells and AR rat model., Materials and Methods: An inflammatory model was induced in RAW264.7 cells by Lipopolysaccharide (LPS) & Interferon-gamma (IFN-γ) stimulation. AR rat model was established using both systemic and local challenges with Ovalbumin (OVA)., Results: In cell experiments, CLO obviously decreased the secretion of cytokines and inhibited the NF-κB signaling pathway activation. In animal experiments, CLO decreased the number of eosinophils in the blood and lowered the levels of cytokines in nasal lavage fluid (NALF). Additionally, CLO inhibited the expression of STAT6, GATA-3, and p-p65, while increasing the expression of STAT4 and T-bet in the nasal mucosa., Conclusion: In AR rat model, CLO may play an anti-inflammatory role in AR rat model by regulating NF-κB and T-bet/GATA-3 signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Acute lung injury (ALI) is an inflammatory reaction produced through various injury-causing factors acting on the lungs in a direct or indirect way, with a high morbidity and mortality rate. A review of clinical experience has revealed that Lysionotus pauciflorus Maxim (LP) has a significant therapeutic effect on ALI. However, the comprehensive effective components of LP are uncertain, and the mechanisms, especially the potential therapeutic target for anti-ALI, are still unknown., Aims of the Study: In vitro and in vivo validation of the pharmacodynamics of LP in the treatment of ALI and exploration of its potential mechanism of action based on network pharmacology, molecular docking and experimental validation., Materials and Methods: Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was employed to identify the ingredients of LP extracts. The potential bioactive ingredients, key targets and signalling pathways were identified by network pharmacology, based on the results of the mass spectrometry analysis. Subsequently, molecular docking was performed on the screened core components and key targets to calculate their molecular binding energies and binding potentials, and to explore the mutual binding modes of small-molecule ligands and large-molecule proteins. Finally, lipopolysaccharide (LPS)-induced RAW264.7 cell model and ALI mice model were used to validate the therapeutic effects and potential mechanism of LP extract towards ALI., Results: From the mass spectrometry results of LP extracts, a total of 89 chemical components were identified, including 46 phenylethanol glycosides, 26 flavonoids, 9 organic acids and their derivatives and 8 other compounds. And furthermore 39 core active components were screened by network pharmacology. The top 10 core components (4 phenylethanol glycosides, 6 flavonoids) have been screened in the composition -target-disease network, and 37 core targets related to LP efficacy were obtained by fitting PPI network analysis. 10 signalling pathways and their targets associated with LP treatment of ALI were obtained by GO/KEGG analysis, indicating that LP could regulate TLR4 and NF-κB signalling pathways through 4 key targets, namely NFKB1, RELA, TLR4 and TNF. The results of the molecular docking procedure indicated a strong affinity, with the binding energies between each component and the target site being less than -6 kcal/mol. The binding modes included Hydrogen Bonds, Pi-Pi interaction, Hydrophobic Interactions, Salt Bridges, Pi-cation interactions. These observations were subsequently validated in vitro and in vivo experiments. The outcomes of in vitro and in vivo experiments demonstrated that LP was effective in reducing the infiltration of inflammatory bacteria in lung tissues and attenuated the expression of pro-inflammatory cytokines in LPS-stimulated mice bronchoalveolar lavage fluid (BALF) and RAW264.7 cells. Furthermore, LP inhibited the expression and phosphorylation of TLR4 protein and NF-κB protein, thus playing a role in the prevention of ALI., Conclusions: In this study, mass spectrometry analysis was combined with biomolecular networks to initially elucidate the potential of LP to treat ALI by modulating the TLR4/NF-κB pathway. This offers a definitive experimental basis for the development of new LP drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A safe and effective vaccine is urgently needed to prevent acute respiratory infections caused by respiratory syncytial virus (RSV). Oral administration offers several advantages, including ease of delivery, minimal stress for vaccine recipients, and greater safety than the systemic injection. In this study, we developed an oral vaccine candidate based on the human adenovirus serotype 5 (Ad5) vector, Ad5-PreF-DS2, encoding a prefusion protein of RSV with a dsRNA as an endogenous adjuvant. We evaluated the immunogenicity and protective efficacy of oral immunization against an RSV challenge in mice, comparing it with those of IM and IN immunizations. Subsequently, we performed an in-depth analysis of the B cell immune response to the oral vaccine. Our findings indicate that oral vaccines elicited a robust antibody response, T-cell response, and B-cell response, and provide effective protection against RSV infection in mice. Importantly, dsRNA adjuvants significantly enhanced T-cell immune responses and increased neutralizing antibody levels when administered via oral vaccination (P < 0.05). These preclinical data demonstrate the capacity of an oral vaccine to induce protective immunity against RSV and support further development of RSV vaccine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chronic insomnia (CI) is a common sleep disorder in middle-aged and elderly individuals. Long-term sleep deprivation can lead to physical, mental, and cognitive damage. Resting-state networks (RSNs) in the brain are closely linked to cognition and behavior. Therefore, we investigated changes in RSNs to explore behavioral and cognitive abnormalities in middle-aged and elderly CI patients. Resting state functional magnetic resonance imaging (rs-fMRI) and independent component analysis were used to study the intrinsic functional connectivity (FC) of the RSNs in 36 CI patients (20 CI with cognitive impairment (CI-I) patients and 16 CI without cognitive impairment (CI-N) patients) and 20 healthy controls (HC). Two-sample t-tests were used to compare RSNs differences between CI and HC groups, as well as between CI-I and CI-N groups. Partial correlation analysis was used to explore the relationship between the significant abnormal brain regions in RSN and clinical scales. Compared with HCs, CI patients showed significant differences in multiple RSNs, and FC values in two brain regions within RSNs were correlated with clinical scales. Furthermore, compared with CI-N group, CI-I group also showed significantly altered FC in multiple RSNs. Moreover, FC values in the right middle frontal gyrus within right frontal parietal network of CI-I patients were negatively correlated with the Mini-Mental State Examination scores. These results may explain hyperarousal, attention deficit and motor impairments in CI patients. Furthermore, the aberrant alterations of RSNs in CI-I patients may play a crucial role in the onset and progression of cognitive impairment in CI patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

2-substituted quinolines are the building blocks for the synthesis of natural products and pharmaceuticals. In comparison with classical methods, dehydroaromatization of 2-substituted-1,2,3,4-tetrahydroquinolines has emerged in recent years as an efficient and straightforward method to synthesize quinolines due to its high atom economy and sustainability. However, existing chemical methods need transition metal catalysts and harsh reaction conditions. Biocatalysis with high efficiency, high selectivity, and mild reaction conditions has become an important method of organic synthesis. We mined a strain Pseudomonas monteilii ZMU-T06 capable of producing monoamine oxidase for the dehydroaromatization of 2-substituted-1,2,3,4-tetrahydroquinolines to synthesize 2-substituted quinolines (8 substrates, yields of 45.7%-48.4%) and then hypothesized the catalytic mechanism, providing a new method for green synthesis of 2-substituted quinolines.

Background: SHEN26 (ATV014) is an oral RNA-dependent RNA polymerase (RdRp) inhibitor with potential anti-SARS-CoV-2 activity. Safety, tolerability, and pharmacokinetic characteristics were verified in a Phase I study. This phase II study aimed to verify the efficacy and safety of SHEN26 in COVID-19 patients., Methods: This was a multicenter randomized double-blind placebo-controlled study. Mild-to-moderate adult patients with COVID-19 were recruited and randomly assigned to the high-dose (400 mg), low-dose (200 mg), or placebo groups (1:1:1). The primary outcome measure was "changes in RNA levels on Day seven (D7)". The second outcome measures were "changes of RNA levels on D3, D5, D10, D28," "Time of clearance of virus.", Results: A total of 91 patients were recruited in this study between December 08, 2022, and January 27, 2023. Twelve patients dropped out due to a lack of examination results. Finally, the data of 79 patients (24 in the placebo group, 31 in the 200 mg group, and 24 in the 400 mg group) were analyzed. No significant differences in the baseline data were observed between the groups. The changes of viral load were significantly higher on D3 (P = 0.0119), and D5 (P = 0.0120) in 400 mg group (vs. placebo group), and the difference value achieved 1.06 log10 copies/mL on D3 and 1.21 log10 copies/mL on D5. No significant difference was found in the viral clearance time between SHEN26 administrating groups and placebo groups. Administration of SHEN26 did not enhance drug-related ADEs and did not induce ADEs, and ADE inducing drug withdrawal, dose reduction, or death. Moreover, SHEN26 did not worsen the renal function., Conclusions: Our findings indicate a better efficacy of a high dose (400 mg) for COVID-19 treatment. These preliminary data on the efficacy and safety provide useful information and a working basis for further verification and development of SHEN26 as a novel oral small-molecule antiviral drug for treating COVID-19., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved and supervised by the Ethical Committee of Shenzhen Third People’s Hospital (approval No: 2022-009), the Ethical Committee of Guangdong Second Provincial General Hospital (approval no: 2022-YWLCYJ-017-02), the Ethical Committee of Shijiazhuang Fifth Hospital (approval no: 2022-YW-004-1), and the Ethical Committee of People’s Hospital of Longhua Shenzhen (approval no: 2022-003Y-02PJ). All interventions were conducted in strict compliance with the protocol and the Declaration of Helsinki (2013). Signed informed consent was obtained from all participants before enrollment. Consent for publication: Not application. Clinical trial registration: ClinicalTrials.gov ID: NCT05676073, https://clinicaltrials.gov/study/NCT05676073 , Registration Date: 2023-01-03. Competing interests: JB, DX, and MY are employees of Shenzhen Kexing Pharmaceutical Co., Ltd, the other authors declare no competing interests., (© 2025. The Author(s).)

Although the concept of bioaccumulation for novel brominated flame retardants (NBFRs) is clear, the process and interfering factors of bioaccumulation are still not fully understood. The present study comprehensively evaluated the occurrence, transfer and interfering factors of NBFRs in a marine food web to provide new thought and perspective for the bioaccumulation of these compounds. The occurrence of 17 NBFRs were determined from 8 water, 8 sediment and 303 organism samples collected from Dalian Bay, China. The trophic magnification factor (TMF), the bioaccumulation factor (BAF) and the biota sediment accumulation factor (BSAF) were calculated in a plankton-mollusk-crustacean-fish based food webs. Results showed that among the 17 target NBFRs, 11 compounds appeared the significant trophic magnification and 2 compounds of decabromodiphenylethane (DBDPE) and octabromotrimethylphenylindane (OBIND) presented the significant trophic dilution. The significant positive correlation was found between the value of BAFs and the trophic level for 15 NBFRs (except DBDPE and OBIND), indicating that the species with high BAFs values were all at high trophic levels. The stable and rapid metabolic rates of DBDPE and OBIND constitute the main reason why they hardly accumulate in high trophic level organisms. The BSAFs of NBFRs in swimming organisms were much higher than that in mollusks and crustaceans, indicating that a large part of NBFRs accumulated from food webs. The significant positive correlation between TMF and BAF was observed in high trophic level organisms, which demonstrates the important role of high trophic level organisms in evaluating the bioaccumulation effect of NBFRs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: B cell immune dysregulation plays a critical role in myasthenia gravis (MG). However, targeted B-cell therapy such as rituximab may result in long-term peripheral B cell clearance and allow for the survival of plasma cells, contributing to frequent infections and relapses. Therefore, we aimed to identify potential novel therapeutic targets that preserve part of B cell function while inhibiting antibody-secreting cells (ASCs)., Methods: The transcriptome of sorted CD19 + B cells obtained from MG patients in active and remission state was performed by RNA sequencing. The hallmark gene NF-kappaB-inducing kinase (NIK/MAP3K14) associated with NF-κB and TNF signaling was identified, and the expression levels of NIK in CD19 + B cells, CD4 + T cells and serum from new-onset MG patients and controls were validated by flow cytometry, qPCR and ELISA. In vitro and in vivo, the effects of NIK inhibitor (B022) on the function of CD19 + B cells and CD4 + T cells were detected under the MG PBMCs, sorted B cells and experimental autoimmune MG (EAMG) rat model, respectively., Results: The expression levels of NIK were upregulated in CD19 + B cells, CD4 + T cells and serum from new-onset MG patients. Notably, increased serum NIK levels were positively correlated with disease severity and decreased with disease remission. NIK inhibitor B022 significantly reduced B-cell activation, proliferation, ASCs differentiation and pathogenic function, as well as CD4 + T cell activation and Th17 cells differentiation in vitro. Intraperitoneal injection of B022 ameliorated the severity of EAMG rats, and reduced proportion of pathogenic B and T cell subsets, antibody levels and postsynaptic membrane damage., Conclusions: Targeting NIK with small molecule kinase inhibitors can effectively shape B cell homeostasis, and exhibit protective effects in the EAMG rat model, which may be an effective novel treatment strategy for MG., Competing Interests: Declarations. Ethics approval and consent to participate: The Ethics Committee of the Affiliated Hospital of Xuzhou Medical University granted approval for this study (XYFY2023-KL471-01), and all participants provided written informed consent. All the animal experimental protocols were approved by the Ethics Committee of Xuzhou Medical University (202410T016). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Polyetheretherketone (PEEK) is widely used in orthopedic and dental implants due to its excellent mechanical properties, chemical stability, and biocompatibility. However, its inherently bioinert nature makes it present weak osteogenic activity, which greatly restricts its clinical adoption. Herein, strontium (Sr) is incorporated onto the surface of PEEK using mussel-inspired polydopamine coating to improve its osteogenic activity. X-ray photoelectron spectroscopy and ion release assay results confirm that different concentrations of Sr are incorporated onto the PEEK substrate surfaces. The strontium-modified PEEK samples show a stable Sr ion release in 35 days of detection. Better results of MC3T3-E1 pre-osteoblasts adhesion, spreading, and proliferation can be observed in strontium-modified PEEK groups, which demonstrates strontium-modified PEEK samples with the improved MC3T3-E1 pre-osteoblasts compatibility. The boosted osteogenic activity of strontium-modified PEEK samples has been demonstrated by the better performed of ALP activity, extracellular matrix mineralization, collagen secretion, and the remarkable up-regulation of ALP, OCN, OPN, Runx2, Col-I, BSP, and OSX of the MC3T3-E1 pre-osteoblasts. Additionally, the strontium-modified PEEK samples exhibit a dose-dependent enhancement of osteoblasts compatibility and osteogenic activity, and the PEEK-Sr10 group shows the best. These findings indicate that strontium-decorated PEEK implants show promising application in orthopedic and dental implants., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Vascular cognitive impairment (VCI) is a significant contributor to dementia, yet the precise mechanisms underlying the cognitive decline associated with chronic cerebral hypoperfusion (CCH) remain unclear. This study investigated the molecular and epigenetic changes in the striatum, a brain region critical for motor function and cognition, following chronic hypoperfusion using a bilateral common carotid artery stenosis (BCAS) model in mice., Methods: RNA-seq was utilized to identify differentially expressed genes (DEGs) associated with hypoperfusion. In parallel, ATAC-seq was used to assess changes in chromatin accessibility within the striatum, providing insight into the epigenome and potential regulatory mechanisms. The integration of these datasets allowed us to correlate chromatin accessibility with transcriptional activity and to identify key transcription factors driving the observed gene expression changes., Results: Analysis of striatum-specific transcriptome revealed significant upregulation of immune response genes, particularly type II interferon signaling, and downregulation of neural activation pathways. Analysis of striatum-specific epigenome showed increased chromatin accessibility at promoters of immune-related genes. Integrated analysis highlighted PU.1 as a key transcription factor in upregulated pathways, while neural pathways lacked epigenetic regulation, revealing distinct molecular responses in the striatum following chronic hypoperfusion., Conclusions: Our findings indicate that upregulated pathways in the striatum following BCAS-induced CCH are driven by epigenetic changes, while downregulated pathways occur independently of these modifications. Additionally, PU.1 plays a critical role in mediating immune responses, offering a potential target for therapeutic intervention., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of Shanghai Medical College of Fudan University (No. 20210302-005). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objective: Deep vein thrombosis (DVT) is a known complication of fractures. This study aimed to explore the genetic causal relationship between DVT and fracture sites., Research Design and Methods: The exposures analyzed in this study included fracture of femur (FFE), fracture of lower leg, including ankle (FLLA), fracture of shoulder and upper arm (FSUA), fracture of forearm (FFO), fracture of rib, sternum and thoracic spine (FRSTS) and fracture of lumbar spine and pelvis (FLSP). DVT as the outcome. A two-sample Mendelian randomization (MR) approach was employed to investigate the genetic causal relationship, and a series of sensitivity analyses were conducted., Results: The findings indicated no genetic causal relationship between FFE ( p  = 0.569, OR 95% CI = 1.001 [0.998-1.003]), FLLA ( p  = 0.371, OR 95% CI = 0.999 [0.995-1.002]), FSUA ( p  = 0.871, OR 95% CI = 1.000 [0.998-1.002]), FFO ( p  = 0.281, OR 95% CI = 1.001 [0.999-1.002]), FRSTS ( p  = 0.346, OR 95% CI = 0.999 [0.996-1.001]) or FLSP ( p  = 0.759, OR 95% CI = 1.000 [0.999-1.002]) and DVT. Sensitivity analyses reinforced the robustness., Conclusions: This study indicate that no genetic causal relationship exists between DVT and fracture site, the observed association may be attributable to non-genetic factors.

Background: Anal fistula surgery often leads to postoperative pain, which can hinder recovery and negatively impact patients' quality of life. This prospective, randomised, controlled trial (RCT) aims to investigate the efficacy of acupuncture in alleviating postoperative pain and reducing the usage of analgesic medications following anal fistula surgery., Methods: This single-centre, patient-blinded, assessor-blinded, placebo-controlled randomised controlled trial (RCT) will be conducted at a tertiary referral hospital. A total of 66 patients with low simple anal fistula will be randomised at a 1:1 ratio to receive either acupuncture or sham acupuncture. The primary outcome is the difference in the numerical rating scale (NRS) pain score before and after acupuncture at 6 hours post surgery. The secondary outcomes include postoperative analgesic usage (Day 0 to Day 7), complications (including infection, urinary retention, and bleeding from Day 0 to Day 7, as well as delayed wound healing and recurrence within 3 months post surgery), sleep quality (PSQI from Day 0 to Day 7), psychological state (SDS and SAS on Day 0, Day 1, and Day 7), and overall recovery quality (QoR-15 on Day 1, Day 3, and Day 7). The statistical analysis of this trial will be conducted using SPSS software, validating the normality of data and the homogeneity of variance, and employing t-tests, Mann-Whitney U tests, chi-square tests, and repeated measures ANOVA to analyze baseline data, primary and secondary outcome indicators., Discussion: This study aims to contribute to the expanding evidence base regarding the role of acupuncture in postoperative pain management. Through a comprehensive assessment of pain relief, analgesic usage, and other recovery-related outcomes, our findings will establish a foundation for standardizing acupuncture protocols specifically tailored for anal fistula surgery patients. The strengths of this trial are rooted in its rigorous randomised controlled trial (RCT) design, comprehensive outcome measures, and focused examination of a clinically significant issue. Ultimately, the findings of this trial have the potential to offer valuable insights into the utility of acupuncture as an adjunctive therapy for postoperative pain management among anal fistula patients, thereby informing future clinical practice and research directions., Trial Registration: This study was registered in the China Clinical Trial Registry on June 1, 2024, with registration number: ChiCTR2400085178., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Myelination is a key biological process wherein glial cells such as oligodendrocytes wrap myelin around neuronal axons, forming an insulative sheath that accelerates signal propagation down the axon. A major obstacle to understanding myelination is the challenge of visualizing and reproducibly quantifying this inherently three-dimensional process in vitro. To this end, we previously developed artificial axons (AAs), a biocompatible platform consisting of 3D-printed hydrogel-based axon mimics designed to more closely recapitulate the micrometer-scale diameter and sub-kilopascal mechanical stiffness of biological axons. First, we present our platform for fabricating AAs with tunable axon diameter, stiffness, and inter-axonal spacing. Second, we demonstrate that increasing the Young's modulus E or stiffness of polymer comprising the AAs increases the extent of myelin ensheathment by rat oligodendrocytes. Third, we demonstrate that the responses of oligodendrocytes to pro-myelinating compounds are also dependent on axon stiffness, which can affect compounds efficacy and the relative ranking. These results reinforce the importance of studying myelination in mechanically representative environments, and highlight the importance of considering biophysical cues when conducting drug screening studies., Competing Interests: A. J. and K. K. are the founders and stock holders of Artificial Axon Labs Inc., which is commercializing artificial axons platform. K. J. V. V holds scientific advisor position at Artificial Axon Labs. A. J. and K. J. V. V., are inventors of patent # 11535826, “Engineered 3D-printed artificial axons”, Daniela Espinosa-Hoyos, Anna E. Jagielska, Huifeng Du, Nicholas X. Fang, Krystyn J. Van Vliet, which covers the materials and assay used in this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2025 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Recipients often suffer from hyperlactatemia during liver transplantation (LT), but whether hyperlactatemia exacerbates hepatic ischemia-reperfusion injury (IRI) after donor liver implantation remains unclear. Here, the role of hyperlactatemia in hepatic IRI is explored. In this work, hyperlactatemia is found to exacerbate ferroptosis during hepatic IRI. Lactate-primed lysine acetyltransferase 8 (KAT8) is determined to directly lactylate mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) at Lys100 and augments PCK2 kinase activity. By using gene-edited mice, evidence indicating that PCK2 exacerbates hepatic ferroptosis during IRI is generated. Mechanistically, PCK2 lactylate at Lys100 acts as a critical inducer of ferroptosis during IRI by competitively inhibiting the Parkin-mediated polyubiquitination of 3-oxoacyl-ACP synthase (OXSM), thereby leading to metabolic remodeling of mitochondrial fatty acid synthesis (mtFAS) and the potentiation of oxidative phosphorylation and the tricarboxylic acid cycle. More importantly, targeting PCK2 is demonstrated to markedly ameliorate hyperlactatemia-mediated ferroptosis during hepatic IRI. Collectively, the findings support the use of therapeutics targeting PCK2 to suppress hepatic ferroptosis and IRI in patients with hyperlactatemia during LT., (© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

A rapid, sensitive, and high-throughput sample preparation method is of paramount significance for proteomics analysis. Here, we report a fast, high-sensitivity MICROFASP method that is capable of completing sample preparation within 1.5 h, enhancing the throughput by over 13 times compared to the previous reports. Protein digestion time was significantly cut from 17 h to 20 min in a limited volume. Simultaneous reduction and alkylation occurred within 30 min. The label-free quantitation intensities of proteins from the fast and conventional MICROFASP methods were highly correlated ( r = 0.91), validating the reliability of the fast-MICROFASP method. When starting with 1 μg of K562 cell lysate, the fast-MICROFASP method identified over 6 times more protein groups and 19 times more peptides than did the iST method. A 96-well plate-based version was developed to process 8 brain tissue samples from APP/PS1 transgenic mice in parallel. Averagely, with only 1 μg of protein lysate, 2826 protein groups ( n = 8, RSD = 0.7%) and 12,972 peptides ( n = 8, RSD = 1.5%) were identified from each sample. Amyloid-beta protein was successfully identified as a highly expressed protein, which shows its potential for detecting diagnostic markers and proteome profiling with low-microgram samples. We anticipate the high-sensitivity 96-well plate-based fast-MICROFASP method will have wide application in high-throughput and rapid preparation of large cohorts of low-microgram samples (e.g., clinical biopsy) for comprehensive proteome profiling. Data are available via ProteomeXchange with the identifier PXD053720.

Objective: The present study aimed to investigate the association between pituitary adenoma (PA) consistency and other measurable tumor characteristics, extent of resection (EOR), postoperative complications, and outcomes., Methods: In total, 507 PA resections were intraoperatively assigned a consistency grade from 1 (cystic/hemorrhagic tumors) to 5 (calcified tumors) based on intraoperative tumor characteristics. Tumor consistency was analyzed in tertiles (grades 1 and 2, grade 3, and grades 4 and 5) to determine associations with tumor characteristics, EOR, recurrence, postoperative outcomes, and complications., Results: The cohort in this study included primarily macroadenomas (93.3%) comprised mostly of nonfunctional PAs (NFPAs) (79.5%), with 77.1% showing suprasellar extension, 16.6% showing infrasellar invasion, and 46.4% showing cavernous sinus invasion (CSI). PA consistency grades were as follows: grade 1 or 2 (40.6%), grade 3 (39.3%), and grade 4 or 5 (20.1%). Compared with grade 1 or 2, higher-consistency PAs were more common in men (p = 0.001) and trended toward lower rates of gross-total resection (GTR) (67.6% vs 53.5%, p = 0.06). Higher PA consistency was predictive of any postoperative complication (OR 1.23, 95% CI 1.05-1.43; p = 0.009), specifically including transient diabetes insipidus (DI) (OR 1.45, 95% CI 1.12-1.85; p = 0.004) and cranial nerve (CN) paresis (OR 3.45, 95% CI 1.56-7.69; p = 0.002). Higher consistency was a strong predictor of CN palsy (OR 3.33, 95% CI 1.52-7.30; p = 0.004) for NFPAs. Higher-consistency PAs were more frequently adrenocorticotropic hormone-positive in both univariable (OR 1.33, 95% CI 1.11-1.60; p = 0.002) and multivariable (OR 1.38, 95% CI 1.11-1.69; p = 0.004) analyses. Higher consistency was associated with lower rates of GTR on stratification by CSI for Knosp grade 3 (p < 0.001) and grade 4 (p < 0.001) PAs, but not in low-grade (Knosp grades 1 and 2) PAs., Conclusions: Tumor consistency is an important consideration for the resection strategy, particularly for PAs with CSI, and a predictor of intraoperative CSF leaks and perioperative complications and outcomes, including EOR, CN paresis, and transient DI.

Objective: To evaluate existing evidence from published systematic reviews for the effectiveness and safety of rehabilitation interventions in adult patients with colorectal cancer., Methods: A comprehensive literature search was conducted using medical/health science databases up to October 2024. Bibliographies of pertinent articles, journals, and grey literature were searched. Three reviewers independently selected potential reviews, assessed methodological quality, and graded the quality of evidence for outcomes using validated tools., Results: Sixty systematic reviews (761 randomized controlled trials) evaluated 5 categories of rehabilitation interventions. Over half of the included reviews (n = 31) were of moderate-high quality. The findings suggest: moderate-quality evidence for exercise interventions for improving physical fitness and quality of life; high-quality evidence for nutritional interventions in reducing postoperative infections; high-quality evidence for multimodal prehabilitation for improved preoperative functional capacity; moderate-quality evidence for nutritional interventions for improving humoral immunity, reducing inflammation, and length of stay; moderate-quality evidence for acupuncture in improving gastrointestinal functional recovery; psychosocial interventions in improving short-term quality of life and mental health, and lifestyle interventions for improved quality of life., Conclusion: Rehabilitation interventions yielded positive effects across multiple outcomes. However, high-quality evidence is still needed to determine the most effective rehabilitation approaches for patients with colorectal cancer.

Timely monitoring of circulating tumor DNA (ctDNA) in serum is meaningful for personalized diagnosis and treatment for lung cancer. Cheap and efficient point-of-care testing (POCT) has emerged as a promising method, especially in a low-resource setting. Herein, (i) a 3D pop-up paper-based POCT device was designed and manufactured via a cheap method; it was used for saving time and efficiently building a biosensor; (ii) a novel cobalt boride nanosheet (CoB NS) nanozyme with abundant groups was used for POCT dual-mode signal transduction and then a portable smartphone/pressure meter to readout; (iii) a user-friendly smartphone app was fabricated for achieving more convenient POCT. Detailly, the dual-mode signal generated was based on the CoB NS with peroxidase activity to catalyze a chromogenic agent to develop color and with catalase activity to catalyze decomposition of H 2 O 2 to O 2 . Density functional theory (DFT) and experimental results showed a good catalysis performance of the CoB NS via studying its five possible catalytic pathways, in which the metal Co is the catalytic active site center that acts as the electron donor and promotes electron transfer between the CoB NS and the adsorbed substrates. Benefiting from that, the proposed method showed good analytical ability in detecting ctDNA. Besides, its accuracy was valued by comparing it with the standard qPCR method to detect real samples from tumor cells and tumor-bearing mice, which showed a consistent result and potential practical applicability of the proposed method for POCT ctDNA. In general, this work not only provided a dual-mode POCT platform that could also be applied for other analytes but also first revealed the nanozyme properties of the CoB NS and inspired its new application from electrocatalysis, energy, etc. to biomedicine.

Purpose: Proton FLASH has been investigated using cyclotron and synchrocyclotron beamlines but not synchrotron beamlines. We evaluated the impact of dose rate (ultra-high [UHDR] vs. conventional [CONV]) and beam configuration (shoot-through [ST] vs. spread-out-Bragg-peak [SOBP]) on acute radiation-induced gastrointestinal toxicity (RIGIT) in mice. We also compared RIGIT between synchrotron-based protons and linac-based electrons with matched mean dose rates., Methods and Materials: We administered abdominal irradiation (12-14 Gy single fraction) to female C57BL/6J mice with an 87 MeV synchrotron-based proton beamline (2 cm diameter field size as a lateral beam). Dose rates were 0.2 Gy/s (S-T pCONV), 0.3 Gy/s (SOBP pCONV), 150 Gy/s (S-T pFLASH), and 230 Gy/s (SOBP pFLASH). RIGIT was assessed by the jejunal regenerating crypt assay and survival. We also compared responses to proton [pFLASH and pCONV] with responses to electron CONV (eCONV, 0.4 Gy/s) and electron FLASH (eFLASH, 188-205 Gy/s)., Results: The number of regenerating jejunal crypts at each matched dose was lowest for pFLASH (similar between S-T and SOBP), greater and similar between pCONV (S-T and SOBP) and eCONV, and greatest for eFLASH. Correspondingly, mice that received pFLASH SOBP had the lowest survival rates (50% at 50 days), followed by pFLASH S-T (80%), and pCONV SOBP (90%), but 100% of mice receiving pCONV S-T survived (log-rank P = 0.047 for the four groups)., Conclusions: Our findings are consistent with an increase in RIGIT after synchrotron-based pFLASH versus pCONV. This negative proton-specific FLASH effect versus linac-based electron irradiation underscores the importance of understanding the physical and biological factors that will allow safe and effective clinical translation., Competing Interests: Declaration of competing interest BWL is a cofounder and board member of TibaRay. SHL reports receiving grants from Nektar Therapeutics, Beyond Spring Pharmaceuticals, and STCube Pharmaceuticals; serving on the advisory board of AstraZeneca and Creatv Microtech; consulting fees from XRAD Therapeutics; and stock options in SEEK Diagnostics (co-founder). TT is currently employed by Hitachi Ltd., (Copyright © 2025. Published by Elsevier Inc.)

Objectives: This study aimed to assess the preferences of breast cancer patients in China for screening services using a discrete choice experiment (DCE) and latent class modeling (LCM). The findings are intended to inform the development of more patient-centered screening programs., Study Design: A cross-sectional, hospital-based survey employing discrete choice experiment methodology., Methods: A total of 278 breast cancer patients were recruited from the Department of Thyroid and Breast Surgery at a tertiary hospital in Guizhou Province. The study evaluated key attributes of screening services, including screening frequency, medical staff experience, referral sources, and out-of-pocket costs, through a DCE questionnaire. A mixed logit model was applied to assess overall patient preferences, while LCM was used to explore heterogeneity among patient subgroups. The development of the DCE questionnaire involved focus group discussions to ensure the relevance of attributes., Results: The analysis revealed that screening frequency, medical staff experience, and out-of-pocket costs were the most significant factors influencing patient preferences. Patients exhibited a strong preference for annual screenings (β = -1.622, p < 0.001) and for screening by experienced medical staff (β = 2.216, p < 0.001). Additionally, lower out-of-pocket costs significantly enhanced willingness to participate (β = -0.211, p < 0.05). LCM analysis identified two distinct patient subgroups: "process-driven" patients, who prioritized lower costs and multi-channel referral options, and "efficiency-driven" patients, who valued timely service and experienced staff., Conclusion: This study emphasizes the diverse preferences of breast cancer patients for screening services and suggests that personalized screening programs could better meet the needs of different patient subgroups. Developing flexible, patient-centered screening programs will be essential to improving participation and satisfaction with breast cancer screening in China. Practical challenges in implementing such personalized approaches should be considered in future policy development., (Copyright © 2025 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Although tamoxifen is commonly utilized as adjuvant therapy for Estrogen Receptor alpha (ERα)-positive breast cancer patients, approximately 30-50% of individuals treated with tamoxifen experience relapse. Therefore, it is essential to investigate additional factors besides ERα that influence the estrogen response. In this study, cross-analysis of databases were performed, and the results revealed a significant association between LINC00626 and ERα signaling as well as increased expression levels of this gene in tamoxifen-resistant cells. LINC00626 is a novel ERα-regulated long non-coding RNA (lncRNA) that has not yet been examined for its potential contribution to endocrine therapy resistance. This study revealed that the upregulation of LINC00626 in breast cancer was associated with poor overall survival in patients. Additionally, ERα signaling was found to transcriptionally regulate LINC00626 expression, thereby promoting cancer progression and enhancing resistance to tamoxifen in breast cancer cells via the regulation of UPF1 expression. Depletion of LINC00626 restored sensitivity to tamoxifen by activating the PERK-ATF4-CHOP signaling pathway via UPF1. These findings support the role of LINC00626 as a potential therapeutic target for combating tamoxifen resistance., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics declarations: All experiments conducted in this study were approved by the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University (Ethical number: YX2023-140). Written informed consent was obtained from all participants prior to their involvement in the study, which was carried out in adherence to the principles outlined in the Declaration of Helsinki. This work has obtained approval for research ethics from the Association of Laboratory Animal Sciences at Anhui Medical University (LLSC20231697), ensuring that all procedures were performed in accordance with ethical guidelines. The study is reported in accordance with ARRIVE guidelines., (© 2025. The Author(s).)

Objective: Disorders of insulin metabolism are strongly associated with a variety of psychological problems. The aim of this study was to investigate the differences in mindfulness levels among type 2 diabetes mellitus (T2DM) patients categorized based on their insulin resistance and β-cell function., Methods: A total of 157 T2DM patients were included in this study and divided into four groups according to their levels of insulin resistance and β-cell function. The Five Facet Mindfulness Questionnaire (FFMQ) was employed to assess the mindfulness levels of the patients. Linear regression models were utilized to investigate the relationships between various T2DM categories and mindfulness levels and dimensions. Furthermore, subgroup analyses of key variables were conducted, and mediation analysis was performed to evaluate the sources of differences., Results: Significant differences were observed among the four groups in terms of total mindfulness scores and in the dimensions of "Describing," "Non-judging of Inner Experience," and "Acting with Awareness" (P < 0.05). Compared to the control group (low HOMA-IR/high HOMA-β), the high HOMA-IR/low HOMA-β group exhibited markedly lower scores in "Non-judging of Inner Experience" (P = 0.02) and "Acting with Awareness" (P < 0.001). The low HOMA-IR/low HOMA-β group demonstrated weaker performance in "Non-judging of Inner Experience" (P = 0.005) and "Describing" (P = 0.002)., Conclusion: Significant differences in mindfulness levels were found to exist among T2DM patients with varying degrees of insulin resistance and β-cell function. Early-stage diabetes patients, particularly those with lower β-cell function or higher insulin resistance levels, may require additional psychological intervention support to enhance their mindfulness and overall well-being., Competing Interests: Declarations. Ethics approval and consent to participate: The present study was conducted in accordance with the principles outlined in the Declaration of Helsinki. Ethical approval was obtained from the Institutional Review Board of The Second Affiliated Hospital of Xuzhou Medical University (Approval Number: [2023] 010107). Informed consent was obtained from all participants prior to their inclusion in the study. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Ionogels have attracted considerable attention as versatile materials due to their unique ionic conductivity and thermal stability. However, relatively weak mechanical performance of many existing ionogels has hindered their broader application. Herein, we develop robust, tough, and impact-resistant mechanically interlocked network ionogels (IGMINs) by incorporating ion liquids with mechanical bonds that can dissipate energy while maintain structural stability. Profiting from the dynamic yet stable nature of the mechanically interlocked networks, IGMINs exhibit high tensile strength (9.6 MPa), fracture energy (39 kJ/m2), and toughness (25.9 MJ/m3), along with a high elongation rate (473%) and excellent impact resistance and shape memory, resulting in overall performance that surpasses most reported ionogels. Furthermore, in the application of strain sensors for monitoring the gait of crawling robots, the toughness and robustness of IGMINs ensure their ability to consistently output stable electrical signals during the stretching and contraction processes, thereby highlighting their practical application potential. Our work provides a new research strategy for toughening ionogels and promotes the development of mechanically interlocked materials., (© 2025 Wiley‐VCH GmbH.)

When dielectrics are hit with intense infrared (IR) laser pulses, transient metalization can occur. The initial attosecond dynamics behind this metallization are not entirely understood. Therefore, simulations are needed to understand this process and to help interpret experimental observations of it, such as with attosecond transient absorption (ATA). In this paper, we present first-principles simulations of ATA based on bulk-mimicking clusters and real-time time-dependent density functional theory (RT-TDDFT), with Koopmans-tuned range-separated hybrid functionals and Gaussian basis sets. Our method gives good agreement with the experiment for the breakdown threshold in silica and diamond. This breakdown voltage corresponds to a Keldysh parameter of approximately one and thus involves a transition to a regime where the dynamics are driven by tunneling. Pumping at an amplitude just below this value causes a mixture of multiphoton and tunneling excitations across the band gap to occur. The computed extreme ultraviolet and X-ray attosecond transient spectra also agree well with the experiment and show a decrease in optical density due to the transient population of the conduction band from the IR field. First-principles approaches such as this are valuable for interpreting the complicated modulations in a spectrum and for guiding future attosecond experiments on solids.

Nitrous oxide (N 2 O) is generally detected by using gas chromatography-mass spectrometry (GC-MS) which has become a popular method in current research and applications. However, N 2 O and CO 2 have the same molecular mass and comparable physical characteristics, posing significant challenges to complete separation and accurate detection of N 2 O. For this purpose, a simple and effective method for detecting nitrous oxide using alkaline washing and GC-MS was proposed. The method first uses an alkaline washing technique to remove CO 2 from the gas sample, followed by the detection of N 2 O using GC-MS. To systematically evaluate the effectiveness of this method in removing CO 2 and detecting N 2 O, a series of experiments were conducted. The experimental results showed that the interference of CO 2 was successfully eliminated, achieving the limit of detection (LOD) for N 2 O of 0.01 μL mL -1 , with the relative standard deviation (RSD) of less than 10%. The method was simple and effective, and does not require specific instruments or chromatographic columns to detect N 2 O from the sample even in the presence of CO 2 , making it highly promising for accurate monitoring of nitrous oxide.

Objectives: Salmonella enterica serovar Enteritidis (S. Enteritidis) is a commonly reported pathogen which adapts to multiple hosts and causes critical disease burden at a global level. Here, we investigated a recently derived epidemic sublineage with multidrug resistance (MDR), which have caused extended time-period and cross-regional gastroenteritis outbreaks and even invasive nontyphoidal Salmonella disease (iNTS) in China., Methods: Whole-genome sequencing and antimicrobial resistance (AMR) testing were applied to 729 Chinese S. Enteritidis isolates in relation to gastroenteritis outbreaks, gastrointestinal-sporadic and iNTS infections, spanning 28 years (1994-2021) in China. Phylogenomic analysis was performed to explore the population structure and evolutionary history of the Chinese isolates within a global context. Molecular investigations of AMR genes, virulence factors, mobile genetic elements and pan-genomes were also performed., Results: The Chinese S. Enteritidis collections exhibited a high level of multidrug resistance (MDR), including high resistance to nalidixic acid (97.67%). Notably, the multidrug resistance rate of iNTS strains has significantly increased over the past decade. Phylogenomic analysis showed that the majority of the Chinese isolates (98.63%) were distributed in the global pandemic lineage L1, while the other lineages were highly continent-specific. Particularly, the Chinese isolates were predominantly distributed in sublineages L1.2 (37.45%) and L1.3 (59.26%), forming two main Chinese clades (MCC1&2). The most recent common ancestor of MCC1&2 dated back to 1944 and 2004, respectively. The lineage L1, especially MCC1&2, harbored the most amount of AMR determinants and virulence genes, which was mainly due to the presence of a hybrid virulence-resistance plasmid and coexistence of different types of AMR plasmids in S. Enteritidis., Conclusions: S. Enteritidis has evolved unique clonal clusters, MCC1&2, with critical MDR in China, which phylogenetically constitute an extension of the globally epidemic lineage and were characterized by distinct genetic traits. These clades have induced extensive outbreaks of gastroenteritis and serious cases of iNTS in China, underscoring the pressing nature and severity of this public health crisis. Implementing the One-Health strategy, longstanding routine surveillance and further genomic epidemiological studies are urgently required to capture epidemics, monitor changes in bacterial populations and determine the consequent risk to global public health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Ltd.)

Objective: To explore the potential of Intravoxel Incoherent Motion Diffusion (IVIM) and Arterial Spin Labeling (ASL) in predicting the short-term effectiveness of post-revascularization for severe atherosclerotic renal artery stenosis., Material and Methods: A retrospective analysis of 88 cases from October 2018 to February 2023 was conducted. Patients were divided into Responder and Non-Responder groups based on renal function outcomes at their last follow-up. Clinical data were compared between the groups, and preoperative functional MRI images were analyzed. ROIs were outlined for the affected and both kidneys. Measurements included ASL-derived renal blood flow (RBF), IVIM's pseudo-diffusion coefficient (D*), perfusion fraction (f), true diffusion coefficient (D), and the conventional apparent diffusion coefficient (ADC).Multivariate logistic regression identified independent clinical predictors of benefit, and a clinical prediction model was developed. Model performance was assessed using Receiver Operating Characteristic (ROC) curves and Decision Curve Analysis(DCA) curves., Results: In the training cohort of 54 non-responders and 34 responders, no quantitative parameters of bilateral kidneys showed statistical significance in predicting Responders (all p > 0.05). Pre-treatment eGFR, presence of diabetes, and the D value of the affected kidney were identified as independent factors for predicting short-term treatment effectiveness. The combined clinical-functional imaging model yielded the higher AUC at 0.796 (95 % CI: 0.690-0.897) . Decision curve analysis further confirmed the better net benefit of combined model., Conclusion: Beyond clinical characteristics, functional MRI had the potential to predict response of stenting for severe atherosclerotic renal artery stenosis., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare no conflicts of interest. The cases for this study were approved by the ethics committee (Ethics Code: 2023105001,Peking University First Hospital) and all participants provided informed consent. The study protocol adhered to the Declaration of Helsinki and the Good Clinical Practice guidelines defined by the International Conference on Harmonization (ICH). The researchers declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author, upon reasonable request., (Copyright © 2025. Published by Elsevier Inc.)

Introduction: Clostridium perfringens (C. perfringens) can cause necrotic enteritis and higher mortality rates in piglets, by impairing the intestinal barrier function. Bacillus amyloliquefaciens 40 (BA40) has showed potential ability to reduce C. perfringens infections, but the mechanisms responsible for its effectiveness remain unclear., Objectives: This study aims to evaluate the impact of BA40 on inflammation induced by C. perfringens and to explain the mechanisms underlying its therapeutic effects. We aim to show how BA40 can bolster piglet health by strengthening the intestinal barrier and regulating immune responses., Methods: We used piglets and cellular models, alongside microbiomics, metabolomic, and transcriptomic analyses, to investigate BA40's impact on C. perfringens-induced inflammation. A model of C. perfringens infection was constructed using piglets and cells to investigate the effect of BA40 on its phenotype. Microbiomics, metabolomics, and transcriptomics analyses were subsequently used to investigate the mechanisms of protection and immune response to BA40 on the intestinal barrier of piglets., Results: Our study revealed significant improvements in piglet health following BA40 administration. Notably, BA40 strengthened the intestinal mucosal barrier and mitigated the inflammatory response triggered by C. perfringens BA40 decreased harmful bacteria and increased beneficial bacteria. Metabolite profiles improved, showing a reduction in harmful substances. Transscriptomics analysis indicated BA40's role in TNF/NF-κB signaling pathway, hinting at its ability to regulate immune responses and reduce intestinal inflammation. Cellular assays further confirmed BA40's capacity to diminish inflammatory cytokine release and encourage the differentiation of anti-inflammatory macrophages., Conclusion: Datasets from the present study demonstrate that BA40 modulates gut microbes and metabolites, inhibits inflammation-related signaling pathways, and maintains gut barrier function. Our findings not only deepen our understanding of the therapeutic capacity of BA40 but also provide a theoretical foundation for the development of probiotics and alternative therapies aimed at improving piglet gut health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

There is little research on anemia and vitamin D deficiency in HIV-exposed uninfected (HEU) children. This study was aimed to describe and compare the prevalence of anemia and vitamin D inadequacy in HEU children and HIV-unexposed uninfected (HUU) children, and to examine the associations of HIV exposure with anemia and vitamin D inadequacy. This was a hospital-based descriptive cross-sectional study nested within the Prevention of Mother-to-Child Transmission (PMTCT) of HIV program in Hunan Province during July and September 2022. The HEU children aged 6 to 24 months were recruited from the PMTCT outpatient clinics located in five Municipal Maternal and Child Health Care Hospitals. The HUU children were recruited from routine child health examination clinics in the same five Hospitals. Questionnaires about children's characteristics and maternal gestational conditions were collected from children's caregivers, and blood samples were collected from all children. Descriptive statistics, Chi-square test, non-parametric rank sum test, and logistic regression were used for analysis. The study population included 336 HEU children and 334 HUU children. The overall prevalence of anemia in the HEU and HUU children was 10.4% and 8.1%, respectively. The median hemoglobin concentrations were 120 (115-126) g/L in the HEU children and 122 (116-129) g/L in the HUU children. Neither prevalence of anemia nor hemoglobin concentration was significantly different between the two groups (P > 0.05). The prevalence of vitamin D inadequacy in the HEU children (19.6% for deficiency and 25.0% for insufficiency) was significantly higher than that of the HUU children (11.4% for deficiency and 16.2% for insufficiency) (P < 0.001). The median 25(OH)D concentration in the HEU children was significantly lower than that of the HUU children (23.80 (13.50-34.08) vs. 32.08 (18.60-39.32) ng/ml) (P < 0.001). HIV exposure in HEU children was significantly associated with an increased risk of vitamin D deficiency (adjusted OR (AOR) 1.72, 95% CI: 1.13-2.61) and vitamin D insufficiency (AOR 1.53, 95% CI: 1.01-2.34), but not with anemia (AOR 0.80, 95% CI: 0.32-2.01). The PMTCT program shall strengthen vitamin D supplementation in HEU children and caregivers shall appropriately extend the outdoor activity time of HEU children to reduce the occurrence of vitamin D inadequacy., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The study protocol was approved by the Ethics Committee of Hunan Provincial Maternal and Child Health Care Hospital (No.2019-S029). The study was conducted in accordance with the Declaration of Helsinki. Written informed consents were obtained from all the caregivers of the included children., (© 2025. The Author(s).)

As global populations become increasingly aged, existing elderly care models are proving insufficient. The development and application of nursing robots have shown potential in addressing the challenges of elder care in aging societies. This perspective outlines current state and potential applications of nursing robots in promoting healthy aging. Given this background, a networked intelligent elderly care model for nursing robots, which integrates technologies such as big data, artificial intelligence, the Internet of Things, and nursing robotics, is proposed. This model would synergistically combine elderly health monitoring, capability assessment, and intelligent allocation functions to revolutionize global elderly care practices and promote healthy aging., Competing Interests: Competing interests: The authors declare that they have no competing interests., (Copyright © 2025 Wenting Ji et al.)

Ubiquitin-specific protease 18 (USP18) is a multifunctional cysteine protease primarily responsible for deconjugating the interferon-inducible ubiquitin-like modifier ISG15 from protein substrates. Here, we report the design and synthesis of activity-based probes (ABPs) that incorporate unnatural amino acids into the C-terminal tail of ISG15, enabling the selective detection of USP18 activity over other ISG15 cross-reactive deubiquitinases (DUBs) such as USP5 and USP14. Combined with a ubiquitin-based DUB ABP, the USP18 ABP is employed in a chemoproteomics screening platform to identify and assess inhibitors of DUBs including USP18. We further demonstrate that USP18 ABPs can be utilized to profile differential activities of USP18 in lung cancer cell lines, providing a strategy that will help define the activity-related landscape of USP18 in different disease states and unravel important (de)ISGylation-dependent biological processes., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

In this study, an efficient membrane composed of polysulfone and graphene oxide was developed and evaluated for its efficacy in chromium adsorption. Characterization of the synthesized membrane involved comprehensive analyses including scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetric analysis (TGA) and Fourier-transform infrared spectroscopy (FTIR) to assess its structural properties. Subsequently, the membrane's performance in removing chromium from aqueous solutions was scrutinized, considering key operational parameters. Response surface methodology (RSM) based on central composite design (CCD) was employed to optimize parameters. Additionally, the pH parameter revealed the most significant (F-value = 184.25) on the amount of chromium removal by the membrane process. The interaction between pH and contact time is the most significant among all interactions, with an F-value of 40.99. Moreover, the high R 2 (97.58%) and adjusted R 2 (95.41%) indicate the model effectively explains variance with minimal overfitting, confirming its strong predictive capability. Under optimized conditions (pH 5, initial concentration of 30 mg/L, and contact time of 40 min), the polysulfone/graphene oxide membrane exhibited an impressive removal efficiency of 81.1%. This study highlights the potential of polysulfone/graphene oxide membranes in effectively separating chromium from aqueous mediums, thereby suggesting a promising avenue for future research in addressing heavy metal pollution.√., Competing Interests: Declarations. Ethics approval: All the authors have read, understood, and have complied as applicable with the statement on “Ethical responsibilities of Authors” as found in the Instructions for Authors and are aware that with minor exceptions, no changes can be made to authorship once the paper is submitted. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Non-pharmaceutical intervention (NPI) policies, ranging from mild measures to total isolation, were implemented worldwide during the COVID-19 pandemic. We adopt a systematic approach to guide policymakers in deploying NPI policies to mitigate the pandemic's effects while balancing their social and economic impacts. Our results show that each NPI has an optimal duration, beyond which its effectiveness plateaus. Stricter policies require longer durations, and when sustained for the optimal period, earlier implementation is more effective. However, when this duration is unattainable, timing becomes critical, as both early and late implementation reduce efficacy. Stringent policies with insufficient durations may perform worse than less restrictive measures applied over the same period, and an NPI policy aimed at minimizing overall healthcare burden under a fixed policy duration may significantly intensify peak-time strains. Finally, as the virus becomes more transmissible and less lethal, the effectiveness gap between stringent and less restrictive policies narrows, with targeted interventions for vulnerable groups outperforming universal strict measures., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objective: Previous experiments have demonstrated that BGM0504, a GLP-1R/GIPR dual agonist drug by molecular dynamics-guided optimization, had enhanced agonistic activity compared to tirzepatide. This study aims to investigate its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in Chinese healthy volunteers., Methods: A randomized, double-blind, placebo-controlled and dose-escalation Phase I study was conducted as follows: a single dose (2.5 mg) and once-weekly administration for 2 weeks to reach target doses (5, 10 and 15 mg) by titration., Results: A total of 40 volunteers received at least one dose of BGM0504 or placebo. The PK profile of BGM0504 was investigated over a wide dose range and supported once-weekly administration. It was observed that C max and AUC of BGM0504 were linearly proportional to the dose from 2.5-15 mg. The change in body weight (%) from baseline in BGM0504 groups was greater than that in the placebo group, with -3.24%, -6.26%, -7.09% and - 8.30% in 2.5, 5, 10 and 15 mg groups, respectively, indicating a certain dose correlation. Meanwhile, the potential roles of BGM0504 in glycaemic control were also observed. The most frequent adverse events reported were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea and abdominal distension)., Conclusion: BGM0504 was generally safe and well tolerated with favourable PK profile and potential role in weight loss was also confirmed. These findings support subsequent development of BGM0504 for type 2 diabetes mellitus (T2DM) and obesity., (© 2025 John Wiley & Sons Ltd.)

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and an important cause of end-stage renal disease (ESRD). However, there is still a lack of effective prevention and treatment strategies in clinical practice. As a metabolic disease, DN is accompanied by renal ectopic lipid deposition, and the deposited lipids further aggravate kidney injury. However, the molecular mechanism of renal ectopic lipid deposition is currently unknown. In this study, we observed changes in lipid droplet (LD)-mitochondria connections in the kidney for the first time. Destruction of LD-mitochondria connection was involved in renal lipid deposition in the kidneys of patients and mice with DN or in high-glucose-treated HK-2 cells. Furthermore, sesamol treatment significantly increased the integrity of the LD-mitochondria connection and ameliorated renal lipotoxicity. Finally, we demonstrated that sesamol maintains the integrity of the LD-mitochondria connection by activating the peroxisome proliferator-activated receptor α (PPARα)/perilipin 5 (PLIN5) signaling pathway. Our study is the first to show that the LD-mitochondria connection may be a target for ameliorating lipid deposition in diabetic kidneys.

Regulatory T cells (Tregs) has been shown to be involved in the induction of transplantation tolerance in numerous models. Our previous work demonstrated that METTL14 loss impaired Treg function and hindered the establishment of transplantation tolerance. However, the underlying mechanisms remain unclear. In this study, we found that METTL14 knockdown in Tregs significantly impaired their regulatory function, leading to poor allograft function and accelerated transplant rejection. Through MeRIP and mRNA sequencing approaches, we discovered that METTL14 deficiency fostered the expression of Sema4D mRNA, a key semaphorin family member with immunoregulatory activity. Methylation of target adenosines reduced Sema4D mRNA degradation, a process mediated by the METTL14-YTHDF2 axis. Inhibition of Sema4D suppressed its interaction with its receptor, thereby preserving Treg immunoregulation capability and prolonging allograft survival through the PAK-STAT5 signaling pathway. Importantly, Sema4D expression in kidney transplant biopsies were negatively correlated with renal allograft survival. In summary, our findings suggest that METTL14 deficiency in Tregs leads to transplant rejection and reveal for the first time that Sema4D may serve as a potential therapeutic target to enhance Treg function in transplantation., Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

Colorectal cancer (CRC) is a prevalent malignant tumor that presents significant challenges to both public health and healthcare systems. The aim of this study was to develop a machine learning model based on five years of clinical follow-up data from CRC patients to accurately identify individuals at risk of poor prognosis. This study included 411 CRC patients who underwent surgery at Yixing Hospital and completed the follow-up process. A modeling dataset containing 73 characteristic variables was established by collecting demographic information, clinical blood test indicators, histopathological results, and additional treatment-related information. Decision tree, random forest, support vector machine, and extreme gradient boosting (XGBoost) models were selected for modeling based on the features identified through recursive feature elimination (RFE). The Cox proportional hazards model was used as the baseline for model comparison. During the model training process, hyperparameters were optimized using a grid search method. The model performance was comprehensively assessed using multiple metrics, including accuracy, F1 score, Brier score, sensitivity, specificity, positive predictive value, negative predictive value, receiver operating characteristic curve, calibration curve, and decision curve analysis curve. For the selected optimal model, the decision-making process was interpreted using the SHapley Additive exPlanations (SHAP) method. The results show that the optimal RFE-XGBoost model achieved an accuracy of 0.83 (95% CI 0.76-0.90), an F1 score of 0.81 (95% CI 0.72-0.88), and an area under the receiver operating characteristic curve of 0.89 (95% CI 0.82-0.94). Furthermore, the model exhibited superior calibration and clinical utility. SHAP analysis revealed that increased perioperative transfusion quantity, higher tumor AJCC stage, elevated carcinoembryonic antigen level, elevated carbohydrate antigen 19-9 (CA19-9) level, advanced age, and elevated carbohydrate antigen 125 (CA125) level were correlated with increased individual mortality risk. The RFE-XGBoost model demonstrated excellent performance in predicting CRC patient prognosis, and the application of the SHAP method bolstered the model's credibility and utility., Competing Interests: Declarations. Competing interests: 14789The authors declare no competing interests., (© 2025. The Author(s).)

As a type of century-old catalyst, the use of iron-based materials runs through the Haber-Bosch process and electrochemical synthesis of ammonia because of its excellent capability, low cost, and abundant reserves. How to continuously improve its catalytic activity and stability for electrochemical nitrogen fixation has always been a goal pursued by scientific researchers. Herein, we develop a free-standing iron-based catalyst, i.e., the iron nanoparticles with zinc oxide nanowire array support (Fe/ZnO NA), which exhibits a high ammonia yield of ∼54.81 μg h -1 mg cat. and a Faradaic efficiency (FE) of ∼9.56% in a 0.5 M potassium hydroxide solution, along with good reusability and durability. Its electrocatalytic ability is superior to that of commercial Fe materials and most reported Fe-based catalysts, thus showing great competitiveness. This is because the ZnO NA not only supplies stable support for the homogeneous dispersion of Fe nanoparticles but also provides a very beneficial synergy to their catalytic activity. The work renews traditional iron-based catalysts and is thus of great significance for promoting the industrialization of electrochemical ammonia synthesis.-1 and a Faradaic efficiency (FE) of ∼9.56% in a 0.5 M potassium hydroxide solution, along with good reusability and durability. Its electrocatalytic ability is superior to that of commercial Fe materials and most reported Fe-based catalysts, thus showing great competitiveness. This is because the ZnO NA not only supplies stable support for the homogeneous dispersion of Fe nanoparticles but also provides a very beneficial synergy to their catalytic activity. The work renews traditional iron-based catalysts and is thus of great significance for promoting the industrialization of electrochemical ammonia synthesis.

The aqueous zinc metal battery holds great potential for large-scale energy storage due to its safety, low cost, and high theoretical capacity. However, challenges such as corrosion and dendritic growth necessitate controlled zinc deposition. This study employs epitaxy to achieve large-area, dense, and ultraflat zinc plating on textured copper foil. High-quality copper foils with Cu(100), Cu(110), and Cu(111) facets were prepared and systematically compared. The results show that Cu(111) is the most favorable for zinc deposition, offering the lowest nucleation overpotential, diffusion energy, and interfacial energy with a Coulombic efficiency (CE) of 99.93%. The study sets a record for flat-zinc areal loading at 20 mAh/cm 2 . These findings provide some clarity on the best-performing copper and zinc crystalline facets, with Cu(111)/Zn(0002) ranking the highest. Using a MnO 2 -Zn full cell model, the research achieved an exceptional cycle life of over 800 cycles in a cathode-anode-free battery configuration.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease that manifests clinically in varying forms depending on the degree of enzyme deficiency. CAH is most commonly caused by 21-hydroxylase deficiency (21OHD) due to mutations in the CYP21A2 gene. Whereas there is a spectrum of disease severity, 21OHD is generally categorized into 3 forms. The classic form encompasses salt-wasting and simple virilizing CAH and the least affected form is termed nonclassic CAH. The classic form of 21OHD occurs in ∼1 in 16 000 births with the most severe salt-wasting cases presenting in the neonatal period with cortisol and aldosterone deficiencies and virilization of external female genitalia. Cortisol deficiency removes normal feedback on the hypothalamic-pituitary-adrenal axis leading to elevations in ACTH and adrenal androgen levels, which often accelerate skeletal maturation, leading to premature epiphyseal growth plate closure. Additionally, supraphysiologic doses of glucocorticoids are necessary to suppress androgen levels, adversely affecting final adult height. This paper highlights a brief history of 21OHD and provides an overview of the genetic basis and pathophysiology of 21OHD., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.)

Recently, two-dimensional (2D) van der Waals (vdW) magnetic materials have emerged as a promising platform for studying exchange bias (EB) phenomena due to their atomically flat surfaces and highly versatile stacking configurations. Although complex spin configurations between 2D vdW interfaces introduce challenges in understanding their underlying mechanisms, they can offer more possibilities in realizing effective manipulations. In this study, we present a spin-orthogonal arranged 2D Fe 3 GaTe 2 (FGaT)/CrSBr vdW heterostructure, realizing the EB effect with the bias field as large as 1730 Oe at 2 K. Interestingly, this structure induces a positive EB under low cooling field, in contrast to conventional phenomena. Moreover, by employing asymmetric field sweeping methods, we effectively manipulate the zero-field cooling EB of the device with a switchable sign and a tunable magnitude. Thus, these findings not only elucidate a distinct mechanism analysis for EB phenomena with perpendicular coupled spin configurations but also hold promise for promoting contemporary 2D spintronic device applications.

The nutritive value of a protein is determined not only by its amino acid composition, but also by its digestibility in the gastrointestinal tract. The interaction between proteins and pepsin in the gastric stage is the first step and plays an important role in protein hydrolysis. Moreover, it affects the amino acid release rates and the allergenicity of the proteins. The interaction between pepsin and proteins from different food sources is highly dependent on the protein species, composition, processing treatment, and the presence of other food components. Coagulation of milk proteins under gastric conditions to form a coagulum is a unique behavior that affects gastric emptying and further hydrolysis of proteins. The processing treatment of proteins, either from milk or other sources, may change their structure, interactions with pepsin, and allergenicity. For example, the heat treatment of milk proteins results in the formation of a looser curd in the gastric phase and facilitates protein digestion by pepsin. Heated meat proteins undergo denaturation and conformational changes that enhance the rate of pepsin digestion. This review provides new ideas for the design of food products containing high protein concentrations that optimize nutrition while facilitating low allergenicity for consumers.

Melatonin (MEL), functioning as a circulating hormone, is important for the regulation of ferroptosis in different health scenarios and acts as a crucial antioxidant in cardiovascular diseases. However, its specific function in ferroptosis related to myocardial ischemia-reperfusion injury (MIRI) remains to be fully elucidated. In our research, we utilized a rat model of MIRI induced by coronary artery ligation, along with a cell model subjected to hypoxia/reoxygenation (H/R). We evaluated relevant genes and proteins by real-time fluorescent quantitative PCR and Western blot analysis. To evaluate myocardial tissue damage and cell injury, we employed cell counting kit-8 assays, flow cytometry, hematoxylin-eosin staining, and 2,3,5-triphenyltetrazolium chloride staining techniques. Our results show that administering MEL notably reduces the concentrations of cTnT, CK-MB, and lactate dehydrogenase in the serum of MIRI rats, mitigates the extent of myocardial infarction, improves the recovery of pathological conditions in myocardial tissues, and reduces the concentrations of Fe 2+ , malondialdehyde (MDA), and reactive oxygen species (ROS) in the myocardial tissue, while also promoting increased glutathione levels. Moreover, MEL can also restore the reduced viability of H9C2 cells caused by H/R or ferroptosis inducers (RSL3), reduce the cellular content of Fe 2+ , MDA, and ROS, and inhibit ferroptosis. Mechanistically, MEL promotes the expression of GPX4 by downregulating the expression of ATF3, thereby inhibiting ferroptosis in cardiomyocytes and ultimately alleviating the process of MIRI. Our study demonstrates that MEL ameliorates MIRI by inhibiting ferroptosis., Competing Interests: Declarations. Ethics approval and consent for publication: All experimental protocols were approved by the Ethics Review Committee of Animal Experiments, and the animals were handled according to the management requirements of the Animal Management Association., (© 2025. The Society for In Vitro Biology.)

Background: Plant diseases cause huge losses in agriculture worldwide every year, but the prolonged use of current commercial fungicides has led to the development of resistance in plant pathogenic fungi. Therefore, there is an urgent need to develop new, efficient, and green fungicides., Results: Twenty-three nootkatone-based thiazole-hydrazone compounds were designed, synthesized, and characterized by Fourier-transform infrared (FTIR), proton ( 1 H) nuclear magnetic resonance (NMR), carbon-13 ( 13 C) NMR, and high-resolution mass spectrometry (HRMS). The antifungal activities results showed that all the target compounds displayed certain antifungal activity against eight tested fungi. Among them, target compounds 3a (88.7%), 3b (92.5%), 3d (88.7%), 3f (84.9%), 3j (88.7%), and 3l (92.5%) were comparable or superior to the positive control boscalid (88.7%) in their inhibitory activities against Physalospora piricola. Meanwhile, target compound 3l had half maximal effective concentration (EC 50 ) values of 18.0172, 18.8236, 16.5914, 18.5044, and 16.5660 μg/mL against Fusarium oxysporum f. sp. cucumerinum, Alternaria solani, Gibberella zeae, Bipolaris maydis, and Colleterichum orbicalare, respectively, exhibiting outstanding and broad-spectrum fungicidal activity. Moreover, a three-dimensional quantitative structure-activity relationship (3D-QSAR) study was carried out to investigate the relationship between the molecular structures of target compounds 3a-3w and their antifungal activity. Furthermore, the target compound 3l [half maximal inhibitory concentration (IC 50 ) = 4.936 μmol/L] showed significantly better inhibitory activity against succinate dehydrogenase (SDH) than boscalid (IC 50  = 6.631 μmol/L). The possible binding mode between target compound 3l and homology-modeling built SDH, was also explored by molecular docking., Conclusion: Target compound 3l deserved further study as the promising candidate for the development of novel SDH inhibitor. © 2025 Society of Chemical Industry., (© 2025 Society of Chemical Industry.)

Intestinal barrier damage causes an imbalance in the intestinal flora and microbial environment, promoting a variety of gastrointestinal diseases. This study aimed to explore the mechanism by which adipose-derived stem cells (ADSCs) repair intestinal barrier damage. The human colon adenocarcinoma cell line Caco-2 and rats were treated with lipopolysaccharide (LPS) to establish in vitro and in vivo models, respectively, of intestinal barrier damage. The expression of inflammatory cytokines (TNF-α, HMGB1, IL-1β and IL-6), antioxidant enzymes (iNOS, SOD and CAT), and oxidative products (MDA and 8-iso-PGF2α) was detected using ELISA kits and related reagent kits. Apoptosis-related proteins (Bcl-2, Bax, Caspase-3 and Caspase-9), tight junction proteins (ZO-1, Occludin, E-cadherin, and Claudin-1) and p38 MAPK pathway-associated protein were detected by Western blotting. In addition, cell viability and apoptosis was determined by a CCK-8 kit and flow cytometry, respectively. Cell permeability was assayed by the transepithelial electrical resistance value and FITC-dextran concentration. The homing effect of ADSCs was detected by fluorescence labeling, and intestinal barrier tissue was observed by HE staining. After ADSC treatment, the level of phosphorylated p38 MAPK protein decreased, the expression of inflammatory factors, oxidative stress and cell apoptosis decreased, the expression of tight junction proteins increased, and cell permeability decreased in Caco-2 cells stimulated with LPS. In rats, ADSCs are directionally recruited to damaged intestinal tissue. ADSCs significantly decreased the levels of D-lactate, diamine oxidase (DAO) and FITC-dextran induced by LPS. ADSCs promoted tight junction proteins and inhibited oxidative stress in intestinal tissue. These effects were reversed after the use of a p38 MAPK activator. ADSCs can be directionally recruited to intestinal tissue, upregulate tight junction proteins, and reduce apoptosis and oxidative stress by inhibiting the p38MAPK signaling pathway. This study provides novel insights into the treatment of intestinal injury.

Objective: Osteoarthritis (OA) represents a condition under the influence of central nervous system (CNS) regulatory mechanisms. This investigation aims to examine the causal association between viral infections of the central nervous system (VICNS) and inflammatory diseases of the central nervous system (IDCNS) and knee osteoarthritis (KOA) at the genetic level., Methods: In this investigation, VICNS and IDCNS were considered as primary exposure variables, while KOA served as the primary outcome. Employing a two-sample mendelian randomization (MR) approach, we conducted an analysis utilizing summary data derived from genome-wide association studies (GWAS). The GWAS summary data pertaining to VICNS and IDCNS were procured from the Finnish consortium, whereas the IEU OpenGWAS database furnished the requisite data for KOA. To ensure the robustness of our genetic causal assessment, a comprehensive array of sensitivity analyses was undertaken, encompassing evaluations of heterogeneity, horizontal pleiotropy, outlier identification, leave-one-out analyses, and assessment of the normal distribution., Results: The results of the MR analyses revealed a suggestive positive genetic causal relationship between VICNS and KOA (P = 0.012, odds ratio [OR] with a 95% confidence interval [CI] of 1.033 [1.007-1.059]). Conversely, the MR analyses did not indicate any evidence of genetic causation between IDCNS and KOA (P = 0.575, OR 95% CI = 0.986 [0.940-1.035]). Importantly, the genetic causal assessment of the exposure and outcome variables did not demonstrate any indications of heterogeneity, horizontal pleiotropy, or outliers. Furthermore, this assessment remained robust against the influence of individual single nucleotide polymorphisms (SNPs) and exhibited adherence to a normal distribution., Conclusion: The result of this study has elucidated a suggestive positive genetic causal link between the VICNS and KOA. However, no such genetic causal relationship was observed between the IDCNS and KOA. These findings substantiate the genetic underpinnings supporting the association between the CNS and OA., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: All authors read and approved the final manuscript. And agree to the publication of the manuscript. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Sulfur dioxide (SO 2 ), being a novel gaseous signaling molecule, exhibits significant potential for application in the field of cardiovascular diseases. SO 2 donors serve as crucial tools for the transportation and regulation of SO 2 in vivo, facilitating the investigation of physiological roles associated with this molecule. However, the current therapeutic SO 2 donors lack the capability to monitor the real-time release of SO 2 , thereby hindering accurate assessment of their therapeutic efficacy and target localization. Herein, we present an activatable chemiluminescent self-reporting SO 2 donor ( CL-SO 2 D ) that can be selectively activated by peroxynitrite (ONOO - ) to release SO 2 and enable real-time visualization of the extent of release through chemiluminescent imaging. In vitro and cellular experiments demonstrate that CL-SO 2 D exhibits high selectivity and signal-to-noise ratio toward ONOO - and effectively facilitates the SO 2 release process. Finally, CL-SO 2 D successfully achieved the response to the mouse inflammatory model and relieved vasoconstriction in zebrafish by releasing SO 2 stimulated by ONOO - . The findings suggest that CL-SO 2 D exhibits impressive attributes in the diagnosis and treatment of SO 2 -related diseases, opening the gateway for developing low-background and high-sensitivity self-reporting SO 2 donors.

Methotrexate (MTX), a widely administered medication for treating an array of tumors and autoimmune disorders, necessitates stringent monitoring due to the potential for severe adverse effects associated with its high dosage. Nevertheless, the existing methods for monitoring MTX are often intricate, time-consuming and incur significant costs. In this work, we constructed a controlled release sensor, harnessing the versatility of a personal glucose meter (PGM), which had been devised for the swift detection of MTX. This innovative approach employed HP-UiO-66-NH 2 as a nanoscale reservoir for glucose encapsulation, with aptamer-conjugated gold nanoparticles (AuNPs@Apt) serving as molecular gates, sealing the pores of the nano-container. Upon the introduction of MTX into the solution, a specific recognition event occurred between the aptamer and MTX, leading to the formation of a stable AuNPs@Apt-MTX complex. This interaction triggered the release of AuNPs@Apt from the surface of HP-UiO-66-NH 2 , allowing glucose to escape, which was then detected by the PGM. This method demonstrated a robust linear response to MTX concentrations spanning from 0.1 μM to 20 μM, with a remarkable detection limit of 0.1 μM. Extensive experiments underscored the platform's exceptional selectivity for MTX detection, coupled with excellent reproducibility and stability, with a detection time of only 30 minutes. Importantly, it had been successfully applied to the analysis of MTX in diluted human serum with satisfactory recoveries. Given its portability and cost-effectiveness, this platform paved a novel avenue for monitoring MTX blood drug levels, offering significant potential for clinical applications and drug monitoring strategies.

Background: Patients with heart failure (HF) are limited by symptoms and have impaired quality of life. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a patient-reported outcome measure that enables evaluation of the effect of HF and the impact of new therapies on health status in patients with HF., Objectives: This prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) assessed the efficacy and safety of finerenone according to baseline KCCQ Total Symptom Score (TSS) and the effect of finerenone on KCCQ-TSS., Methods: FINEARTS-HF tested the efficacy of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone, compared with placebo, in patients with HF with mildly reduced ejection fraction/preserved ejection fraction. The primary endpoint was the composite of cardiovascular death and total worsening HF events. The KCCQ was completed by patients at randomization and at 6, 9, and 12 months after randomization. Change in KCCQ-TSS was a key secondary endpoint. Patients were stratified by KCCQ-TSS tertiles at baseline. The association between KCCQ tertile and clinical outcomes was evaluated using semiparametric proportional-rates models for total events and Cox models for time-to-first-event data, and the effects of finerenone vs placebo on the primary endpoint were assessed across tertiles of KCCQ-TSS., Results: Of the 6,001 participants in FINEARTS-HF, 5,986 (99.8%) had baseline KCCQ-TSS recorded (median score 69.8 of a possible 100; higher score = better health status). Lower (worse) KCCQ-TSS was associated with a higher risk of the primary endpoint. Finerenone, compared with placebo, reduced the risk of the primary endpoint across the range of KCCQ-TSS: tertile 1 (score 0-<57): RR: 0.82 (95% CI: 0.68-1.00); tertile 2 (57-<81): 0.88 (95% CI: 0.70-1.11); tertile 3 (81-100): 0.88 (95% CI: 0.69-1.14) (P interaction  = 0.89). Compared with placebo, finerenone significantly improved KCCQ-TSS from baseline with a mean difference at 12 months of 1.62 points (95% CI: 0.69-2.56 points) (P < 0.001). Numerically fewer finerenone-treated patients experienced clinically meaningful deterioration, and more had improvements in KCCQ-TSS., Conclusions: Finerenone significantly reduced HF events and improved health status in patients with HF and mildly reduced ejection fraction/preserved ejection fraction across the spectrum of KCCQ-TSS at baseline. (Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone on Morbidity [Events Indicating Disease Worsening] & Mortality [Death Rate] in Participants With Heart Failure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke] Greater or Equal to 40% [FINEARTS-HF], NCT04435626; Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure; EudraCT 2020-000306-29)., Competing Interests: Funding Support and Author Disclosures The FINEARTS-HF trial was funded by Bayer. Dr Yang has received Global CardioVascular Clinical Trialists (CVCT) Young Trialist Grant and travel grants from AstraZeneca and Bayer. Dr Atherton has received other support from Bayer, during the conduct of the study; and has received other support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Novo Nordisk, Vifor Pharma, and Merck Sharp and Dome, outside of the submitted work. Dr Chiang has received personal fees from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Menarini, Merck Sharp and Dohme, Novartis, Pfizer, and Sanofi. Dr Chopra has received modest speaker fees from Boehringer, AstraZeneca, Novartis, Pfizer, Novo Nordisk, Glenmark, Sun, Mankind, Lupin, Alembic, JB, Reddy’s, Intas, Eris, and Cipla, outside of the submitted work. Dr Comin-Colet has received personal fees from Bayer, during the conduct of the study; has received grants from Novartis, Vifor Pharma, AstraZeneca, and Orion Pharma; and has received personal fees from Bayer, Boehringer Ingelheim, Vifor Pharma, Novartis, AstraZeneca, and Orion Pharma, outside the submitted work. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Cytokinetics, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca and Vifor; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Saraiva has received grants or fees for working on clinical trials, consultancy, advisory board or steering committee membership, and other activities from AstraZeneca, Novo Nordisk, Bayer, Boehringer Ingelheim, Novartis, Merck Sharp and Dohme, and Janssen. Dr Claggett has received personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket; and has served on a data safety monitoring board for Novo Nordisk. Dr Desai has received institutional research grants (to Brigham and Women’s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, and Zydus. Dr Lam has received research support from Novo Nordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a cofounder and non-executive director of Us2.ai. Dr Senni has served on advisory boards for, served as a consultant for, and received honoraria from Novartis, Abbott, Merck, Merck Sharp and Dohme, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. Dr Shah has received research grants from National Institutes of Health (U54 HL160273, X01 HL169712, R01 HL140731, R01 HL149423), AHA (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Voors’ employer has received consultancy fees and/or research support from Adrenomed, Anacardio, AstraZeneca, Bayer AG, Bristol Myers Squibb, Boehringer Ingelheim, Corteria, EliLilly, Merck, Moderna, Novartis, Novo Nordisk, Roche Diagnostics, and SalubrisBio. Dr Zannad has received personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, Bristol Myers Squibb, CVRx, Cambrian, Cardior, Cereno Pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, Novo Nordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2; has stock options at G3Pharmaceutical; has equities at Cereno, Cardiorenal, and Eshmoun Clinical research; and is the founder of Cardiovascular Clinical Trialists. Dr Pitt is a consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Lexicon, Bristol Myers Squibb, KBP Biosciences, Sarfez Pharmaceuticals, Pharmaceuticals, SQinnovations, G3 Pharmaceuticals, Sea Star medical, Vifor Prointel, and Brainstorm Medical; has stock/stock options in KBP Biosciences, Sarfez Pharmaceuticals, Pharmaceuticals, SQinnovations, G3 Pharmaceuticals, Sea Star medical, Vifor Prointel, and Brainstorm Medical; and has U.S. Patent 9931412-site specific delivery of eplerenone to the myocardium, U.S. Patent pending 63/045,783 Histone modulating agents for the prevention and treatment of organ failure. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Drs Jhund and McMurray are supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund. Dr Jhund has received speakers’ fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, and Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc, and Roche Diagnostics; his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk; and is Director of GCTP Ltd. Dr Solomon has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GlaxoSmithKline, Ionis, Lilly, MyoKardia, National Institutes of Health/NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr McMurray has received payments through Glasgow University from work on clinical trials, as well as consulting fees and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, British Heart Foundation, National Institute for Health–National Heart, Lung, and Blood Institute, Boehringer Ingelheim, SQ Innovations, and Catalyze Group; has received personal consultancy fees from Alnylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, Bristol Myers Squibb, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corp; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals and Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, Translational Medicine Academy; has served on the Data Safety Monitoring Board for WIRB-Copernicus Group Clinical Inc; and is a director of Global Clinical Trial Partners Ltd. Drs. Kolkhof, Viswanathan, Lage, and Rohwedder are employees of Bayer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)